Date Published: September 31, 2010
Publisher: Impact Journals LLC
Author(s): Bengt F. Belgardt, Jan Mauer, Jens C. Brüning.
Activation of stress-kinase signaling has recently been recognized as an important pathophysiological mechanism in the development of diet-induced obesity, type 2 diabetes mellitus and other aging-related pathologies. Here, c-Jun N-terminal Kinase (JNK) 1 knockout mice have been shown to exhibit protection from diet-induced obesity, glucose intolerance, and insulin resistance. Nonetheless, the tissue-specific role of JNK1-activation in the development of the metabolic syndrome has been poorly defined so far. Recently, it was demonstrated that JNK1 signaling plays a crucial role in the central nervous system (CNS) and in the pituitary to control systemic glucose and lipid metabolism partially through regulation of hormones involved in growth and energy expenditure.
The insulin/insulin-like signalling pathway is highly conserved throughout the animal kingdom. Whereas its predominant role in mammals is the control of metabolic homeostasis and its deregulation leads to the development of diabetes mellitus, lowering insulin/insulin-like signalling in c. elegans, d. melanogaster and m. musculus has been implicated in lifespan extension [1-5].
In 2002, the group of Gökhan Hotamisligil revealed that mice deficient for the stress mediator c-Jun N-terminal Kinase (JNK) 1 are protected from the development of high fat diet-induced obesity and glucose intolerance, as well as insulin resistance . Nonetheless, it remained unclear, in which tissue(s) JNK1 might act to impair energy and glucose homeostasis under conditions of diet-induced obesity.
In the last year, JNK1 has been conditionally inactivated in several peripheral classically insulin-sensitive tissues including adipose tissue, muscle and liver [24-26] (Figure 1). Nevertheless, none of these mouse models fully recapitulated the protection from obesity and diabetes observed in conventional knockout mice opening the possibility that JNK1 activation also in the CNS may contribute to its effects on energy and glucose metabolism.
During metabolic phenotyping, we noticed increased energy expenditure in JNK1∆Nes mice, even when corrected for lean body mass . Accordingly, we found increased circulating levels of the thyroid hormone thriiodothyronine (T3), in the presence of elevated concentrations of its releasing hormone, namely thyroid stimulating hormone (TSH), a finding which was independently reported by Roger Davis and colleagues [31,34]. However, hypothalamic expression of thyroid releasing hormone (TRH), which itself represents the upstream regulator for expression and release of TSH in the pituitary, was unchanged .
When exposed to HFD, JNK1∆Nes mice not only demonstrated protection against systemic glucose intolerance and insulin resistance, but also showed reduced hepatic steatosis, and importantly, an anti-inflammatory gene expression pattern in the adipose tissue .